Antiphlogistic Activity of Iproniazid

Abstract

Iproniazid was found to inhibit formalin-induced oedema of the foot, dextran-induced oedema and cotton-pellet-induced granulomatous tissue in the rat. The presence of the adrenals was essential for the antiphlogistic activity. The antiphlogistic action was not accompanied by any antipyretic effect. Inhibition of formalin-induced oedema was also observed with phenylbutazone and with salicylamide.Little is known about the therapeutic efficacy and mechanism of action of iproniazid in rheumatoid arthritis. In the opinion of Scherbel (1957, 1958a and b), the main effect of the drug is to improve the psychic condition of patients. However, Banghart (1958), using *higher doses, frequently obtained objective improvement, but he also observed side-effects in a large number of patients and frequently had to reduce the dose or even suspend treatment with the drug. This paper describes a pharmacological investigation of the mechanism of action of iproniazid in artificially induced inflammatory states. METHODS Antiphlogistic ActionFormaldehyde-induced Oedema. -Oedema was induced in the hind foot by the injection of 0.1 ml. of a 3% solution of formaldehyde into the plantar aponeurosis of male rats (150 to 250 g. Cotton-pellet-induced Granulomata.-The weights of the granulomata, which formed after the subcutaneous insertion of cotton pellets weighing 18 lo 19 mg. into male rats weighing 70 to 80 g., were estimated by the method of Meier, Schuler, and Desaulles (1950). Administration of iproniazid was started the day after implantation, and either 50 or 100 mg./kg. of the drug was given subcutaneously daily for six days. On the eighth day after implantation the rats were killed, the granulomata removed, freed from the cotton nucleus and wetweighed. Antipyretic ActionThis was tested by the subcutaneous injection of the drugs into rabbits which received immediately afterwards an intravenous injection of 1 ml. of antityphoid vaccine mixed with 1 ml. of a 20% suspension of brewers' yeast. Rectal temperatures were measured by thermocouples. RESULTSFormaldehyde-induced Qedema. Iproniazid in doses of 200( mg. /kg. almost completely inhibited a formaldehyde-induced oedema (Fig. 1). With doses of 100 and 50 mg./kg., the inhibition was less marked but statistically significant. The intensity of the antiphlogistic action was expressed quantitatively by measuring the area enclosed between the curves for the control and treated animals ( Figs. 1 and 2). The logarithm of the dose and the surface (expressed in arbitrary units) of these areas are clearly proportional (Fig. 3).The antiphlogistic effects of phenylbutazone and salicylamide are represented in Fig. 2

Some Inhibitors of Histamine‐induced and Formaldehyde‐induced Inflammation in Mice

“…Methocarbamol, amidopyrine and phenylbutazone, however, were highly active, whereas the four aryloxypropionates tested and sodium acetylsalicylate were moderately active. The activity of phenylbutazone confirmed the observations of Setnikar, Salvaterra & Temelcou (1959). In the cortisone-maintained adrenalectomized mice both sodium salicylate and B.C.…”

“…Selye (1949) has shown that in the adrenalectomized rat both cortisone and adrenocorticotrophic hormone are effective in antagonizing the reaction to formaldehyde. It has been reported by Setnikar, Salvaterra & Temelcou (1959) that the swelling of the rat foot caused by an injection of formaldehyde can be partially prevented by iproniazid, phenylbutazone and salicylamide. Recently, Buch (1959) has shown that various phenylpropylcarbamates are effective in reducing the reaction to formaldehyde.…”

Recent Research in the Field of 5-Hydroxytryptamine and Related Indolealkylamines

“…Other areas containing histamine but less 5-HT exhibit this response weakly [910J; g) subcutaneous injection into the rat paw of dextran or turpentine oil produces a significant reduction (from 0·75 to 0-22-0-28 /kg/g) of the 5-HT content not only in the injected paw but also in the opposite untreated paw [1183bJ_ Sustainers of the theory that multiple agents are involved in the pathogenesis of the anaphylactoid reaction object that substances which produce this reaction release 5-HT as well as histamine from skin tissues [908,847,539]; that higher doses of BOL or LSD are required to block anaphylactoid reaction than to block oedema produced by 5-HT [847b]; that while Dibenamine® regularly inhibits the oedema produced by 5-HT, and pyrilamine that produced by histamine, both drugs are necessary to block the oedema-producing action of ovomucoid [1010]; that pretreatment with the MAO-inhibitor iproniazid does not affect dextran oedema, contrary to expectation [36,846,1092]; that oedema produced by 5-HT, even after the highest doses which can be tolerated, is never as marked as that obtained with substances capable of producing an anaphylactoid inflammation; that oedema produced by histamine, dextran or formaldehyde is inhibited to a great extent by pretreatment with glucagon (1 mg/kg), whereas 5-HT oedema is not significantly changed [713 b] ; that 48/80 even given repeatedly does not produce any change in the urinary excretion of 5-HIAA and rats given compound 48/80 in increasing doses for 8 days excrete as much 5-HIAA after injection of reserpine as the untreated controls do [618b];…”

Rats Resistant to the Dextran Anaphylactoid Reaction

“…Tests involving the inhibition of dextran-induced oedema in rats have been described for the quantitative evaluation of antihistamines (Stucki & Thompson, 1958;KMt6 & Gozsy, 1960c and anti-inflammatory compounds (Setnikar, Salvaterra & Temelcou, 1959). The present results show that, when a strain of rat which contains some non-reactors is used, then by chance the resistant animals may be unequally distributed between the test and control groups.…”

“…Tests involving the inhibition of dextran-induced oedema in rats have been described for the quantitative evaluation of antihistamines (Stucki & Thompson, 1958;KMt6 & Gozsy, 1960c and anti-inflammatory compounds (Setnikar, Salvaterra & Temelcou, 1959 (Kabat & Berg, 1953)-then it is likely that this antibody to dextran is lacking in non-reactor rats. The difference between the reactions to dextran in rats of the two types used in the present study is in any case genetically controlled.…”